There is much concern about the possibility of renewed use of biological agents in intentional acts of bioterrorism, and the necessity to protect the public's health if renewed attempts were to become a reality. To meet this challenge, new avenues for basic research on the pathogenesis of and host defense to Category A agents of Bioterrorism have become available. In this Program Project Grant application in response to initiatives on Biodefense and Emerging Infectious Disease Research, a group of scientists with previous experience with Francisella tularensis, hantaviruses, and Yersinia pestis will collaborate in a comprehensive project that will study: 1) the mechanisms of survival and replication of Y. pestis in macrophages; Project 1, James Bliska. 2) the novel mechanisms of F. tularensis interaction with cells of the inflammatory and innate immune systems; Project 2, Martha Furie. 3) the biochemical role of the prokaryotic SmpB-SsrA quality control system of Y. pestis and F. tularensis with particular emphasis on antibacterial therapy and its utility in anti-infective drug discovery; Project 3, Wali Karzai. 4) the hantavirus proteins that regulate cellular IFN responses and define mechanisms of signaling pathway regulation by pathogenic hantaviruses; Project 4, Erich Mackow. 5) the virulence factors of Y. pestis and F. tularensis and to elucidate the mechanisms of virulence factor assembly and secretion by these pathogens; Project 5, David Thanassi. The Research Projects will be supported by three Cores. Core A will deal with all administrative, development, and laboratory security matters and it will be headed by the PI, Jorge Benach. Core B is the Microarray and Bioinformatics Core headed by Bruce Futcher will produce spotted DNA microarrays for the genomes of F. pestis and F. tularensis, and make custom human microarrays. Core B will provide advice and assistance with all microarray experiments; and with all data interpretation with state of the art Bioinformatics. Core C will produce monoclonal antibodies for all of the Projects. A multidisciplinary approach including aerosol infections of mice in a BSL3Ag setting is expected to be a powerful tool for the basic research needs of these agents, and for the development of the diagnostic and therapeutic aspects of this Program Project.